The overall goal of the proposed work is to develop new agent for the treatment of human disease of retroviral origin, especially acquired immune deficiency syndrome (AIDS). A two-pronged attack combinant chemical synthesis and biological evaluation is planned. With continuous feedback from the biological side to guide and facilitate the chemical effort. The focus of the proposal is on nucleosides, since two of these, 3'-azidothymidine (AZT) and 2',3'- dideoxycytidine (ddCyd) are currently the most promising investigational drugs for the clinical treatment of AIDS. An ongoing program of chemical synthesis of nucleoside analogues exist in this laboratory and useful in vitro and in vivo models have been developed in other laboratories of the Dana-Farber Cancer Institute to rapidly test antiretroviral agents, such as AZT, as they become available. In this context we plan to synthesize (a) analogues of which the azido group is replaced by other functionalities with a pi-orbital structure, (b) analogues of AZT based on bioisosteric replacement of ring atoms and (c) analogues of 2',3'- dideoxyguanosine (ddAdo) and 2',3'-dideoxyguanosine (ddGuo) in which the heterocyclic moiety is altered to prevent catabolic inactivation by adenosine deaminse or purine nucleoside phosophosylase. Biological evaluation of the nucleosides synthesized in the protect will include testing of their ability to (a) block retroviral replication in uninfected cells: (b) prevent cytopathic effect such as the formation of giant cells (syncitia): (c) suppress viremia and prolong survival in mice infected with Rauscher leukemia virus complex, which is a convenient laboratory model for the evaluation of candidate anti- AIDS drugs in vivo. 5'-Triphosphate esters of nucleosides that prove active in vito will be synthesized chemically and tested for the ability to competitively inhibit reverse transcriptase activity in a cell-free away. Any compound showing sufficiently in vivo activity against Rauseher leukemia virus in mice to warrant consideration for eventual clinical trial will be subjected to additional pharmacological and toxicological testing.